Hepatitis C virus (HCV) infection is a major health concern that leads to chronic liver disease in a substantial number of patients. This viral disease is transmitted sexually and parenterally by contaminated blood, blood products, and contaminated needles. Current treatments for HCV infection are limited to immunotherapy with interferon-α, either alone, or in combination with ribavirin [1-(β-D-ribofuranosyl)-1H-1,2,4-triazole-3-carboxamide).
The HCV virion is a small, enveloped positive-strand RNA virus in the Flaviviridae family. The genome contains a single open reading frame encoding a polyprotein of over 3,000 amino acids, which is cleaved to generate the mature structural and non-structural viral proteins. The single open reading frame is flanked by 5′ and 3′ non-translated regions of a few hundred nucleotides in length, which are important for RNA translation and replication. The translated polyprotein contains the structural core and envelope proteins (E1, E2, p7) at the N-terminus, followed by the nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B). The mature structural proteins are generated via cleavage by the host signal peptidase. The junction between NS2 and NS3 is autocatalytically cleaved by the NS2/NS3 protease, while the remaining four junctions are cleaved by the N-terminal serine protease domain of NS3 complexed with NS4A. The NS3 protein also contains the NTP-dependent helicase activity, which unwinds duplex RNA during replication. The NS5B protein possesses RNA-dependent RNA polymerase activity, which is essential for viral replication. Unlike Hepatitis B virus (HBV) or Human Immunodeficiency Virus (HIV), no DNA is involved in the replication of HCV.
United States published patent application no. 2005-0009737 discloses that 1-(2-deoxy-2-fluoro-2-C-methyl-β-D-ribofuranosyl)cytosine (1) is a potent and selective anti-HCV agent. The synthetic procedures for preparing compound 1 are inefficient with overall yields at or below 4%.
A key intermediate for preparing compound 1 is 3,5-di-O-acyl-2-fluoro-2-C-methyl-D-ribono-γ-lactone (2).

A number of synthetic routes for preparing intermediate 2 have been disclosed in PCT/US2005/025916, but these synthetic routes have the shortcomings of high manufacturing costs and technical difficulties for commercial scale manufacturing. The use of heavy load of asymmetric dihydroxlyation catalyst (AD-mix-β), fluorinating agent diethylaminosulfur trifluoride, and the Wittig reagent, etc., are the major cost drivers. The use of highly toxic reagents, such as AD-mix-β, highly reactive reagent such as diethylaminosulfur trifluoride, and chromatographic isolation of intermediates, etc. contribute to scale up difficulties.
Accordingly, a novel and cost effective method for the preparation of intermediate 2 is required.